PART

II

Clinical Syndromes and Cardinal Features of Infectious Diseases:

Approach to Diagnosis and Initial Management

SECTION A: Septicemia, Toxin- and Inflammation-Mediated Syndromes

11

The Systemic Inflammatory Response Syndrome (SIRS),

Sepsis, and Septic Shock
Judith A. Guzman-Cottrill, Beth Cheesebrough, Simon Nadel, and Brahm Goldstein

Sepsis remains a major cause of morbidity and mortality among

children.14 Sepsis-associated mortality in children has decreased
from 97% in 19665 to 9% among infants in the early 1990s.6 A
recent population-based study of United States children with
severe septicemia (bacterial or fungal infection with at least one
acute organ dysfunction) reported a mortality rate of 10.3%.7
Although this represents a significant improvement over past
decades, severe sepsis remains one of the leading causes of death
in children, with over 4300 deaths annually (7% of all deaths
among children) and estimated annual total costs of $1.97
billion.8
In a seminal study, Watson etal.8 analyzed the impact of age,
sex, birthweight, underlying disease, and microbiologic etiology
on the incidence, mortality, and hospital costs of children who
develop septicemia using 1995 hospital discharge and population
data from seven states. Table 11-1 shows the annual incidence, case
fatality, and national estimates of severe sepsis by age. The incidence is highest in infants (5.16 per 1000), falls significantly in
older children (0.20 per 1000 in 10- to 14-year-olds), and also
exhibits a sex difference, being 15% higher in boys than in girls
(0.60 versus 0.52 per 1000, P < 0.001).8 Overall hospital mortality
was 10.3%, or 4383 deaths nationally (6.2 per 100,000 population).8 Of interest, about 50% of the cases had an underlying
disease and over 20% were low-birthweight neonates. The most

TABLE 11-1. Annual Incidence, Case Fatality, and National

Estimates of Severe Sepsis by Age

Age

Incidence
(Per 1000
Population)

National
Estimate
of Cases

Case
Fatality
(%)

National
Estimate
of Deaths

<1 yeara
028 daysb
29364 daysb
14 yearsa
59 yearsa
1014 yearsa
1519 yearsa

5.16
3.60
1.56
0.49
0.22
0.20
0.37

20,145
14,049
6,096
7,583
4,168
3,836
6,633

10.6
10.3
13.5
10.4
9.9
9.6
9.7

2135
1361
774
786
413
368
644

All children

0.56

42,364

10.3

4383

National estimates are generated from the seven-state cohort using state
and national age- and sex-specific population estimates from the National
Center for Health Statistics and the United States Census.
b

Results for these ages are based on data from the five states (MA, MD,
NJ, NY, and VA) in which neonates could be identified (n = 6349 or 66%
of the entire seven-state cohort).
From Watson RS, Carcillo JA, Linde-Zwirble WT, etal. The epidemiology
of severe sepsis in children in the United States. Am J Respir Crit Care
Med 2003;167:695701.

2012 Elsevier Ltd, Inc, BV

common infections were respiratory tract (37%) and primary

bloodstream infections (BSIs) (25%).8 The mean length of hospital stay was 31 days, and the cost was $40,600 per admission.8

DEFINITIONS
An international panel of experts in the fields of adult and pediatric septicemia and clinical research proposed the first set of
specific definitions and criteria for the components of the sepsis
continuum that can be applied consistently in the pediatric population in 2005.6 These definitions were used again in the international guidelines for management of sepsis and septic shock.9 The
consensus definitions for systemic inflammatory response syndrome (SIRS), infection, sepsis, severe sepsis, septic shock, and
multiple organ dysfunction syndrome in children are listed in Box
11-1. It is important to recognize that these definitions were meant
for use in the design, conduct, and analysis of large, multicenter,
international therapeutic trials rather than as a clinical tool at the
bedside. It is clear that, given the intra- and inter-individual differences in the time course of disease progression, these definitions often have limited clinical utility.
The diagnosis and thus the definition of septic shock in children
can be challenging. Children often maintain blood pressure until
severely ill;10 while there is no requirement for systemic hypotension in order to make the diagnosis of septic shock as there is in
adults, a recent expert review committee recommends early recognition of septic shock in premature neonates, infants, and children
using clinical examination, not biochemical tests.11 Shock can
occur long before hypotension occurs in children. Thus, shock can
be diagnosed clinically before hypotension occurs by clinical
signs, which include hypothermia or hyperthermia, altered mental
status, and peripheral vasodilation (warm shock) or vasoconstriction with capillary refill >2 seconds (cold shock).11 Hypotension
is a sign of late and decompensated shock in children and is
confirmatory of shock state if present in a child with suspected
or proven infection.12 Although there are distinct clinical presentations and classifications of shock in children (e.g., warm and
cold shock; fluid-refractory and catecholamine-resistant shock),
septic shock is defined as septicemia in the presence of cardio
vascular dysfunction (i.e., severe sepsis with cardiovascular
dysfunction).6

ETIOLOGY
Several factors influence the potential pathogens causing septicemia in children, including age, host immune status, and
geographic location at the time of infection. In addition, organisms causing community-onset infections differ from those
acquired in the hospital setting. During the neonatal period,
common bacterial causes include group B streptococci and
enteric bacilli, such as Escherichia coli. Other less common pathogens include enterococci, Listeria monocytogenes, Staphylococcus

97

PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION A Septicemia, Toxin- and Inflammation-Mediated Syndromes

BOX 11-1. Definitions of Systemic Inflammatory Response Syndrome,

Infection, Sepsis, Severe Sepsis, and Septic Shock
SYSTEMIC INFLAMMATORY RESPONSE
SYNDROME (SIRS)
The presence of two or more of the following criteria, one of
which must be abnormal temperature or leukocyte count:
Corea temperature of >38.5C or <36C
Tachycardia, defined as a mean heart rate >2 SD above
normal for age in the absence of external stimulus, chronic
drugs, or painful stimuli; or otherwise unexplained persistent
elevation over a 0.5- to 4-hour time period or for children <1
year old: Bradycardia, defined as a mean heart rate <10th
percentile for age in the absence of external vagal stimulus,
beta-blocker drugs, or congenital heart disease; or otherwise
unexplained persistent depression over a 0.5-hour time period
Mean respiratory rate >2 SD above normal for age or
mechanical ventilation for an acute process not related to
underlying neuromuscular disease or the receipt of general
anesthesia
Leukocyte count elevated or depressed for age (not
secondary to chemotherapy-induced leukopenia) or >10%
immature neutrophils
INFECTION
A suspected or proven (by positive culture, tissue stain, or
polymerase chain reaction test) infection caused by any pathogen
or a clinical syndrome associated with a high probability of
infection. Evidence of infection includes positive findings on
clinical exam, imaging, or laboratory tests (e.g., white blood cells
in a normally sterile body fluid, perforated viscus, chest X-ray
consistent with pneumonia, petechial or purpuric rash, or purpura
fulminans)
SEPSIS
SIRS in the presence of or as a result of suspected or proven
infection
SEVERE SEPSIS
Sepsis plus the following: cardiovascular organ dysfunction,
acute respiratory distress syndrome (ARDS), or two or more
other organ dysfunctions
SEPTIC SHOCK
Sepsis and cardiovascular organ dysfunction
a

Core temperature must be measured by rectal, oral, or central catheter

probe.
From Goldstein B, Giroir B, Randolph A. International pediatric sepsis
consensus conference: definitions for sepsis and organ dysfunction in
pediatrics. Pediatr Crit Care Med 2005;6:28.

aureus (including methicillin-resistant Staphylococcus aureus) and

Streptococcus pneumoniae. Advances in neonatology and survival of
extremely- and very-low-birthweight infants affect the epidemiology of hospital-associated neonatal sepsis. The use of central
venous catheters (CVCs) and other foreign bodies further predispose these already compromised neonates to pathogens such as
coagulase-negative staphylococci, S. aureus, less common gramnegative bacilli, and Candida spp. Viral neonatal sepsis may be
indistinguishable clinically from bacterial infection. Viral pathogens include herpes simplex virus, enteroviruses, respiratory
syncytial virus, and influenza virus.
Beyond the neonatal period, S. pneumoniae and Neisseria meningitidis are common causes of sepsis in otherwise healthy children. Haemophilus influenzae type b (Hib) should be considered in
the incompletely vaccinated child. In 2005, only 9 cases of invasive Hib disease in children <5 years of age were reported in the

98

U.S.13 In 2008, this increased to 30 cases.14 Since the routine

administration of the heptavalent pneumococcal conjugate
vaccine in 2000, the overall incidence of invasive pneumococcal
disease in children <5 years of age has declined by 76%.15 Other
organisms include S. aureus and Streptococcus pyogenes (also causing
toxic shock syndrome), Salmonella spp., and rickettsia in certain
geographic regions (Rocky Mountain spotted fever and ehrlichiosis). In hospitalized infants and children with indwelling CVCs,
coagulase-negative staphylococci, S. aureus, gram-negative bacilli,
and Candida spp. are important causes of sepsis due to central line
associated bloodstream infection (CLABSI).
Children with underlying immunodeficiency states can develop
septicemia due to the same pathogens as healthy children;
however, some conditions predispose to additional organisms.
Neutropenic cancer patients with mucositis are at risk of sepsis
due to the Enterobacteriaceae, other gram-negative bacilli such as
Pseudomonas aeruginosa, and alpha-hemolytic (viridans) streptococci. The last are associated with acute respiratory distress syndrome (ARDS) and can cause meningitis.16,17 As most oncology
patients have indwelling CVCs, they also remain at risk for the
typical CLABSI pathogens. Other conditions increase risk of sepsis
due to certain pathogens, e.g., acquired immunodeficiency virus
(AIDS) for S. pneumoniae, P. aeruginosa, S. aureus, and Hib; anatomic or functional asplenia (including sickle-cell disease) for
encapsulated organisms such as S. pneumoniae, Salmonella spp.,
Hib, and N. meningitidis; and cyclic neutropenia for Clostridium
species.

PATHOPHYSIOLOGY
If a microbe gains access to the intravascular compartment, the
host activates defensive mechanisms. Transient bacteremia without
significant clinical consequences occurs commonly in healthy
children. In others, probably depending on the age and immunocompetence of the patient, the virulence and number of pathogens in the blood, and the timing and nature of a therapeutic
intervention, the hosts systemic inflammatory response ensues
and can progress independently, despite successful eradication of
the microbe. Although infection is a major cause of the systemic
inflammatory response syndrome (SIRS), a number of other entities, including trauma, ARDS, neoplasm, burn injury, pancreatitis,
and dysfunctional macrophage activation, are also recognized
causes.
Most pathophysiologic consequences of the sepsis syndrome
result from an imbalance between pro- and anti-inflammatory
mediators in combination with microbial toxins.18 In children,
severe sepsis arises from coordinated activation of the innate
immune response.19 This response, triggered by diverse pathogens,
is multifaceted.1820 Once triggered, the response leads to secretion
of pro- and anti-inflammatory cytokines, activation and mobilization of leukocytes, activation of coagulation and inhibition of
fibrinolysis,21,22 and increased apoptosis.23 As a result of coagulation activation, thrombin generated promotes fibrin deposition in
the microvasculature and also exacerbates ongoing inflammation
by direct and indirect mechanisms.18 Although evolutionarily
designed to limit microbial dissemination, overexuberant innate
inflammatory processes may be detrimental, resulting in cardiac
dysfunction, vasodilation, capillary injury, and micro- and macrovascular thromboses. Despite antimicrobial therapy and intensive supportive care, these processes frequently lead to organ
dysfunction, thrombotic complications, long-term neurologic
morbidity, or death (Table 11-1).1,24
The clinical manifestations of sepsis are the result of systemic
inflammation and include abnormal temperature regulation,
flushed warm skin, widened pulse pressure, tachycardia, tachypnea, metabolic acidosis (elevated serum lactate, decreased base
excess), renal and/or hepatic dysfunction, thrombocytosis, and
leukocytosis. As the syndrome progresses, multiorgan failure,
including acute respiratory failure, hypotension, myocardial
failure, decreased neurologic function, oliguric or anuric renal
failure, hepatic failure, leukopenia, anemia, and thrombocyto
penia, can ensue and can lead to death.

The Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and Septic Shock

CLINICAL AND LABORATORY FINDINGS

Fever, tachycardia, and tachypnea are the most common physiologic abnormalities associated with sepsis, even though they are
insensitive and nonspecific. Other clinical signs include decreased
tone, diminished activity, pale or grey skin color, prolonged capillary refill time, and poor feeding or sucking.25 Biochemical markers
of inflammation may one day prove to be more objective and
reliable than physiologic findings; however, no biochemical
marker has been confirmed to be robust enough to use for the
definitive diagnosis of sepsis or for tracking response to therapy
and disease progression. Early recognition of septic shock depends
on clinical recognition, as there are no reliable biochemical tests
available to date.11 Early treatment with antibiotics and fluid resuscitation has been demonstrated clearly to reduce both morbidity
and mortality.11,12,26

Clinical Signs
The earliest clinical sign of clinical infection is age-dependent
changes in body temperature.27 In immune-competent children
the earliest sign is fever. In immune-compromised children and
premature infants the earliest sign can be hypothermia or fever.27
Fever in association with changes in a childs behavior, such as an
infants loss of smiling or playfulness (especially after fever has
been controlled with antipyretic therapy), are signs of serious
infection, which may benefit from antibacterial, antiviral, or antifungal therapy.2830
Tachycardia is a useful sign of sepsis in the neonate born at
term,31 as is tachycardia and/or tachypnea in older children.27
Fever can account for some tachycardia, as each 1C increase can
result in an increase in heart rate of 10%; however, the heart rate
and respiratory rate should become normal for age when fever is
controlled with antipyretic therapy or falls spontaneously.27 Heart
rate >150 beats/minute in children and >160 beats/minute in
infants, and respiratory rates >50 breaths/minute in children
and >60 breaths/minute in infants are associated with increased
mortality risk and commonly presage the development of septic
shock.6 A minimum mean arterial pressure of >30mmHg is
considered absolutely the lowest tolerable blood pressure in
the extremely premature infant.11,32 Specific hemodynamic abnormalities at the time of coming to medical attention have been
associated with increasing mortality: eucardia (1%), tachycardia/
bradycardia (3%), hypotension with capillary refill <3 seconds
(5%), normotension with capillary refill >3 seconds (7%), hypotension with capillary refill >3 seconds (33%).11

Laboratory Findings
Numerous biologic markers of sepsis in children have been
studied; however, none has independent high positive or negative
predictive value for decision making in clinical practice based on
evidence of prospective clinical trials.27,33 Biomarkers that are commonly used clinically include: the total peripheral white blood
cell (WBC) count,34,35 platelet count, erythrocyte sedimentation
rate (ESR), base excess/base deficit, lactate,36,37 procalcitonin
(PCT),3841 C-reactive protein (CRP),4245 and interleukin-6 (IL6).41,46,47 Many tests and biologic markers currently under study
and development are promising and include specific rapid antigen
assays,48 polymerase chain reaction tests,4951 genomic testing (for
guiding therapy and determining host response),52,53 and proteomic testing (for identification of differentially expressed proteins and peptides).5458 Use of combinations of tests may improve
independent predictive values.59

MANAGEMENT
Antimicrobial Therapy
Empiric antimicrobial therapy for severe sepsis should be administered urgently, targeting likely causative pathogens (Table 11-2).
Important considerations when selecting a regimen include: the

11

TABLE 11-2. Suggested Initial Antimicrobial Choices for Empiric

Therapy in Infants and Children with Suspected Sepsisa
Age or Clinical Situation

Antimicrobial Agent(s)

Neonate (community-onset)

Ampicillin + gentamicin

Neonate (hospital-onset)

Vancomycin + gentamicin or cefotaximeb

Child (community-onset)

Cefotaxime or ceftriaxone + vancomycin

Child (hospital-onset)

Vancomycin + anti-pseudomonal
penicillin or ceftazidime or carbapenemb

Skin or soft-tissue
involvement

Vancomycin or semi-synthetic penicillin +

clindamycin

Toxic shock syndrome

Vancomycin or semi-synthetic penicillin +

clindamycin

Neonatal HSVc

Acyclovir

Rocky Mountain spotted fever

Doxycycline

Ehrlichiosis
a

Antimicrobials should be modified as laboratory data is available and

based on clinical course.
b

Antimicrobial should be based on patient-specific risk factors and local

antimicrobial susceptibility trends (see text).
c

HSV, herpes simplex virus.

childs age, community versus hospital acquisition, host immune

status, and penetration into affected or at-risk tissues and compartments (such as central nervous system). In U.S. cities, as many
as 76% of invasive, community-associated S. aureus isolates can
be methicillin resistant.60 Vancomycin should be included in the
empiric regimen if S. aureus is suspected. Once the causative
organism is isolated and antibiotic susceptibilities are available,
antimicrobial therapy is adjusted appropriately. When possible,
broad-spectrum agents (such as vancomycin, third-generation
cephalosporins and carbapenems) should be discontinued to
minimize the emergence of multidrug-resistant organisms in
the patient and spread in the patients environment. If Escherichia
coli or Klebsiella spp. (or other gram-negative bacilli in certain
hospital settings) are isolated, the organism is tested for extendedspectrum -lactamase (ESBL) production. Carbapenems are the
treatment of choice for serious infections with ESBL-producing
organisms.61

Supportive Care
Effective treatment of sepsis and septic shock is dependent on
prompt recognition and initiation of supportive as well as specific
therapy. The basic principles of initial critical care include ensuring
adequate circulation, airway patency, and gas exchange. The interventions required to achieve these goals depend on the specific
physiologic state of the patient at the time of presentation. Shock
that occurs during sepsis results from decreased intravascular
volume, maldistribution of intravascular volume, and/or impaired
myocardial function, all of which can occur at different times
during the course of septic shock.62 Children with sepsis who
receive early aggressive fluid resuscitation (>40mL/kg in the first
hour with isotonic intravenous fluids) demonstrate improved survival without increased risk of noncardiogenic pulmonary edema
or ARDS.63,64
Determination of when, what type, and how much pharmacologic support is needed in a patient with septic shock requires
careful consideration of many factors. These factors include the
patients clinical state (e.g., capillary refill time, urine output,
peripheral versus core temperature gradient), information
obtained from monitoring devices (heart rate, blood pressure,
central venous pressure, pulmonary artery pressure, cardiac output,
stroke volume, and systemic vascular resistance), and knowledge
of basic drug effects (including dopamine, norepinephrine, epi
nephrine, and phenylephrine) in the setting of septic shock.
All references are available online at www.expertconsult.com

99

PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION A Septicemia, Toxin- and Inflammation-Mediated Syndromes

Septic shock causes multisystem organ dysfunction, and it is

important to evaluate and treat abnormalities in other organ
systems, including the kidney and gastrointestinal tract. Patients
with acute renal failure may require renal replacement therapy.
The gastrointestinal tract is vulnerable to disturbances such as
hemorrhage, ileus, brush border atrophy, and translocation of
enteric organisms into the blood. Additionally, early institution of
nutritional support, particularly enteral feeding, may ameliorate
gastrointestinal atrophy, bacterial translocation, and improve
multiorgan function.65
Maintaining tight control of serum glucose has been shown to
be beneficial in some studies in critically ill adult patients and is
currently being evaluated in children.66

Endotoxin Physiology and Antiendotoxin Therapy

Endotoxin is one of the most important bacterial components
contributing to the inflammatory process. Levels of endotoxin
correlate directly with severity of meningococcal disease and other
forms of sepsis, and with elaboration and release of inflammatory
mediators. Endotoxin upregulates TNF-, IL-1 and IL-6, complement and coagulation pathways. Endotoxin also can be found in
the presence of critical illness, not related to gram-negative
sepsis,67,68 where its presence appears to be related to severity of
disease and outcome. It is postulated that the presence of endotoxin in the blood in these circumstances is related to altered gut
permeability.
The assumption that the inflammatory process is related to the
presence of endotoxin in the bloodstream is based on the finding
that the pathophysiology of gram-negative sepsis can be reproduced by administration of purified endotoxin or a variety of
endotoxin-free inflammatory mediators, which are upregulated by
endotoxin.
A variety of antiendotoxin strategies have been proposed in
the management of severe sepsis, including agents that bind
to and neutralize endotoxin, enhance endotoxin clearance,
or inhibit the interaction of endotoxin with its receptors (see
Table 11-3).

Cytokine Physiology and Anticytokine Therapy

Cytokines have a central role in the pathogenesis of bacterial infection and sepsis. Cytokines coordinate a wide variety of inflammatory reactions at the tissue level. The cytokine network can be
divided roughly into a proinflammatory arm and an antiinflammatory arm. Prominent proinflammatory cytokines are
TNF- and IL-1. Anti-inflammatory cytokines, of which IL-10 is a
well-studied example, inhibit the synthesis of proinflammatory
cytokines and exert several direct anti-inflammatory effects on
different cell types. The action of proinflammatory cytokines can
be further inhibited by naturally occurring soluble inhibitors, such
as soluble TNF receptors type I and type II which inhibit TNF
activity, soluble IL-1 receptor type II, and IL-1ra, which both
inhibit IL-1 activity.
The plasma concentrations of cytokines are rapidly dynamic
and vary greatly in patients with sepsis. Some patients who fulfill
the clinical criteria for SIRS may not have detectable levels of
proinflammatory cytokines in their circulation because they are
studied late in the septic process.69 This may explain why the
cytokines TNF-, IL-1, IL-12, and IFN-, which according to
animal models play a central role in the pathogenesis of septic
shock, are not consistently correlated with disease severity or
outcome in patients with septic shock.
Infection models that use an initially localized source of infection such as pneumonia and peritonitis have suggested that pro
inflammatory cytokines have a crucial role in host defense against
bacterial infection. Neutralization of endogenous TNF- during
murine pneumonia caused by either gram-positive or gramnegative bacteria resulted in an accelerated course of the infection,
and was associated with greater outgrowth of bacteria in the lungs,
and decreased survival.70 Conversely, the elimination of IL-10
improved survival of murine pneumonia and reduced the

100

bacterial load within the pulmonary compartment.71 Evidence for

anticytokine therapies is summarized in Table 11-3.

Immunoparalysis
Induction of anti-inflammatory pathways to inhibit excessive
proinflammatory activity can be demonstrated in most patients
with sepsis. This has led to the concept of compensatory antiinflammatory response, following SIRS in time course.72 In addition, shortly after the onset of a septic event, a refractory state
develops that is characterized by a relative inability of host inflammatory cells to respond to usual proinflammatory stimuli (such
as endotoxin challenge).73 The diminished responsiveness involves
monocytes, granulocytes, and lymphocytes. Although the mechanisms that underlie immunoparalysis have not been explained
completely, it is conceivable that anti-inflammatory cytokines,
particularly IL-10 and transforming growth factor- (TGF-) are
involved.
It has been proposed that immunoparalysis could contribute to
the increased susceptibility to nosocomial infection and late mortality of patients who survive the acute sepsis. As a result, strategies
aiming to restore immune function have been developed and
evaluated partially in patients with sepsis. Cytokines are able to
reverse monocyte deactivation in vitro and in animals; IFN-
and granulocyte-macrophage colony-stimulating factor (GM-CSF)
have been studied with the results summarized in Table 11-3.7476

Arachidonic Acid Metabolism and Inhibitor Therapy

Products of the cyclooxygenase (COX) and lipooxygenase pathways of arachidonic acid metabolism include leukotrienes, prostaglandins, and thromboxane. These products appear to play a
major role in diminishing systemic vascular resistance and causing
platelet aggregation, membrane lysis, and increased capillary permeability, which are the hallmarks of SIRS and shock. Drugs that
interfere with these pathways have been tested as treatments for
sepsis and are summarized in Table 11-3.

Immune Globulin Intravenous (IGIV) Therapy

Immune globulin intravenous (IGIV), like IFN- and GM-CSF, can
be regarded as a treatment method aimed to improve host defense.
Although plasma immune globulin concentration may be reduced
in patients with sepsis, the use of IGIV therapy is not supported
by randomized clinical trials. Indeed, no individual well-designed
trial has been undertaken in adults with sepsis. A small nonblinded study in 21 patients with streptococcal toxic shock syndrome showed a reduced mortality (6% versus 34%, P = 0.02),
suggesting possible benefit in pyrogenic exotoxin-mediated
shock.77 Results of the International Neonatal Immunotherapy
Study (INIS trial), which enrolled 3493 infants, are expected to be
published in the near future.78

Corticosteroids
Since the 1960s, investigators have attempted to modulate the
inflammatory response to sepsis with corticosteroids, given at
doses much higher than normal physiologic concentrations. These
studies failed to show a beneficial effect of glucocorticoids in
patients with sepsis.79,80 However, more recent investigations
indicate that glucocorticoids in much lower doses (supposedly
inducing less immunosuppressive effects) could be of benefit to
patients with septic shock.
Adrenal failure is common in critical illness, particularly in
vasopressor-dependent septic shock. High baseline total serum
cortisol together with a low response to a corticotropin stimulation test is correlated with a poor outcome in sepsis.81 Several
studies in children and adults with septic shock have demonstrated abnormalities of control of adrenal corticosteroid secretion
over the course of illness.82,83
Various randomized controlled trials comparing hydrocortisone
to placebo have been performed in septic shock. There is general

The Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and Septic Shock

11

TABLE 11-3. Evidence for Potential Therapies for Severe Sepsis and Shock
Agent

Mechanism of Action

Studies

E5

Murine monoclonal antibody against core

elements of endotoxin

915 adults with confirmed gram-negative sepsis in a multicenter

placebo-controlled trial; no statistical difference in mortality96

HA-1A

Humanized monoclonal antibody against lipid A

moiety of endotoxin

621 adults with presumed gram-negative bacillary shock in placebocontrolled trial; significantly higher mortality in those treated97,98

ANTIENDOTOXIN

THERAPIES

269 children with meningococcal septicemia in a placebo-controlled trial;

reduced mortality by 33% (nonsignificant)99
rBPI21

Bactericidal-permeability inducing factor

(neutrophil granule protein that can neutralize
endotoxin)

393 children with meningococcal septicemia in placebo-controlled trial; no

statistical difference in mortality; fewer treated patients required multiple
amputations (3.2% vs. 7.4%)100

Statin therapy101

Elevates HDL levels (HDL binds to and neutralizes

endotoxin); modifies T-lymphocyte activity;
enhances expression of endothelial nitric oxide;
modulates inflammatory cell signaling and
release of cytokines; has antioxidant effects

69,168 Canadian adults in matched cohort study; reduced incidence of

sepsis in treated overall and in high-risk groups, i.e., those receiving
corticosteroids, patients with diabetes mellitus and malignancy102

Plasmapheresis or
exchange transfusion

Removes endotoxin and other inflammatory

mediators

Anecdotal reports of good outcomes103110

Polymyxin B hemoperfusion

Binds and neutralizes endotoxin

64 adults with intra-abdominal infection in randomized 2-session

hemoperfusion vs. conventional therapy; reduced vasopressor
requirements and reduced 28-day mortality (32% vs. 53%)111

ANTICYTOKINE THERAPIES
Monoclonal antibody
against TNF-

Removes TNF-

Pooled data from clinical trials; reduced mortality 3.5%112

Soluble TNF- receptor

constructs

Mops up TNF-

Most studies failed to demonstrate an effect. One adult placebo-controlled

trial showed increased mortality in patients receiving high-dose dimeric
type II TNF- receptors113

Afelimomab

F(ab ) 2 fragment of murine monoclonal

antibody binds to TNF-

Adults with severe infection and high IL-6 levels in multicenter trial; relative
risk of death reduced 11.9% and more rapid improvement in organ
dysfunction scores114

Recombinant IL-1ra

Inhibits IL-1 activity

Administered in continuous infusion; no reduction in mortality115,116

ARACHIDONIC
Ibuprofen

Inhibits cyclooxygenase pathway

ACID METABOLISM THERAPIES

455 adults with sepsis in randomized study; reduced prostaglandin I2,

thromboxane levels, and lactic acidosis; no reduction in acute respiratory
distress syndrome or mortality117
Adults with sepsis and hypothermia; reduced 30-day mortality118

Pentoxifylline

ANTICOAGULANT THERAPIES
Recombinant tissue factor
pathway inhibitor (TFPI)

Inhibits phosphodiestaerase resulting in

suppression of TNF-, IL-1, and IL-10;
prevents endothelial cell dysfunction;
stimulates release of tissue plasminogen
activator; attenuates thromboxane release

51 adults; improved scores of organ dysfunction119

Inhibits factor Xa and possibly exerts other

effects on inflammatory mediators distinct
from its effect on coagulation

Improved outcome in septic animals122

Adult phase II study; trend toward reduced mortality and no increase in
adverse effects123
1754 adults with severe sepsis in phase III multicenter study, no effect on
28-day mortality; possible benefit in subset with severe communityacquired pneumonia124

Neonatal studies; reduced all-cause mortality120,121

2100 adults with severe community-acquired pneumonia in a prospective

randomized study (CAPTIVATE) to assess 28-day mortality; results
pending
Antithrombin

Activated protein C (aPC)

Inhibits thrombin, factors IXa and Xa; binds to

endothelial cells modulating the inflammatory
response

Continuous infusion in adults with sepsis; reduced IL-6 levels and

diminished CRP125

Inactivates factors Va and VIIIa

1690 adults with severe sepsis in multicenter trial; reduced 28-day mortality127

2314 adults with severe sepsis in randomized trial; absolute reduction in

90-day mortality of 7.6%; difference was negated in those receiving
concomitant heparin for prophylaxis of deep vein thrombosis126
477 children with severe sepsis in a randomized, placebo-controlled trial;
halted early for failure to demonstrate benefit in any endpoints and
appearance of increased risk of hemorrhagic complications in children
<60 days of age128

Continued

All references are available online at www.expertconsult.com

101

PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION A Septicemia, Toxin- and Inflammation-Mediated Syndromes
TABLE 11-3. Evidence for Potential Therapies for Severe Sepsis and Shockcontd
Agent

Mechanism of Action

Studies

Tissue plasminogen
activator (tPA)

Inhibits intravascular thrombosis by catalyzing

conversion of plasminogen to plasmin

Rescue therapy in children with meningococcal septicemia;

unacceptable level of adverse events, including fatal intracranial
haemorrhage129

THERAPIES
BB-882

TARGETING THE ENDOTHELIUM

Antagonizes platelet-activating factor (PAF

activates endothelial cells and amplifies the
release of inflammatory mediators)

100 adults with severe infection; no reduction in mortality and no

improvement in hemodynamic or respiratory scores130

TCV-309

Antagonizes PAF

98 adults; reduced organ dysfunction; no effect on mortality131

BN52021

Antagonizes PAF

609 adults with severe sepsis; statistically insignificant reduction in

mortality132

Platelet-activating factor
acetyl-hydrolase
(PAF-AH)

A secreted plasma protein that inactivates PAF

and other oxidized phospholipids

127 adults with severe sepsis; reduced all-cause mortality133

1261 adults with severe sepsis in a multicenter, international trial; halted
early for failure to demonstrate improved 28-day mortality or secondary
endpoints134

agreement that hydrocortisone supplementation improves the

hemodynamic condition of vasopressor-dependent septic shock.84
What remains more controversial is the definition of adrenal
insufficiency, the optimal dose and timing of corticosteroid supplementation, whether this should then be tapered slowly, and
the impact of corticosteroid supplementation on outcome. A multicenter, randomized, placebo-controlled trial of 499 patients with
septic shock85 found that hydrocortisone did not improve overall
survival or in the subgroup of patients who did not have a response
to corticotropin, although shock was reversed more quickly in the
hydrocortisone-treated group than in the placebo group.
Although no study has evaluated the efficacy of corticosteroids
in children with sepsis, several well-designed trials conducted in
children with bacterial meningitis, most of whom had bacteremia
when enrolled, have shown that early administration of dexamethasone was associated with significant reduction in hemodynamic instability in the 6 hours after initiation of antibiotic
therapy.86

Anticoagulant Therapies
Virtually all patients with sepsis have coagulation abnormalities.
These abnormalities can vary from subclinical alterations in clotting times, to full-blown disseminated intravascular coagulation
(DIC). Because of the recognized interactions between inflammation and coagulation, manipulation of the coagulation cascade
would appear to be an attractive target for new therapies (see
Table 11-3).

Therapies Targeting the Endothelium

Endothelial dysfunction appears to be pivotal as the primary
pathologic feature of severe sepsis. Restoration of endothelial
function by interventions to reduce endothelial cell injury and
dysfunction are being developed (see Table 11-3).

Nitric Oxide Balance

Activation of the inflammatory response results in elaboration of
a number of mediators with direct effects on vasomotor tone.
Nitric oxide (NO), bradykinin, histamine, and prostaglandin I2
(PGI2) can all decrease vascular tone and cause hypotension. NO
is a highly diffusible compound that activates soluble guanylate
cyclase in smooth-muscle cells. This converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which
relaxes the smooth-muscle cell via a protein kinase, by promoting
calcium entry into the sarcoplasmic reticulum.87
The inflammatory response in sepsis, including increased NO
production, can result in endothelial cell dysfunction affecting
vascular smooth muscle. The resulting effects on organ perfusion

102

may be instrumental in the pathogenesis of the multiple organ

dysfunction syndrome seen in septic shock, which is associated
with increased morbidity and mortality. The implication of NO
in the vascular hyporesponsiveness and cardiac depression of
sepsis supports the hypothesis that blockage or reduction of NO
production may produce clinical benefit in patients with sepsis
(see Table 11-3).
However, there are many animal models of sepsis in which
various inhibitors of NO production have demonstrated potentially harmful effects as well as potential benefit. It has become
clear, however, that nonspecific NO inhibitors cause detrimental
effects secondary to reduced organ perfusion, elevation of pulmonary artery pressures, and increased renal vascular resistance88,89 as
well as increased capillary permeability, increased lactic acidosis,
and hepatic toxicity.90 This is likely to be due to inhibition of
baseline NO production which is essential for control of organ
perfusion under normal circumstances.

Innate Immune Responses and Toll-Like

Receptors (TLRs)
The most exciting new development in sepsis research in the past
years is the discovery of TLRs as signal-transducing elements of
multiple antigens and the rapidly unfolding picture of TLRs as
essential in the innate immune response to infection.91
Upon first encounter with a microorganism, the innate immune
system can distinguish between different classes of pathogenic
bacteria, viruses, and fungi. The innate immune system can recognize conserved motifs on pathogens that are not seen on higher
eukaryotes. These motifs have been referred to as pathogenassociated molecular patterns or PAMPs, whereas their binding
partners on immunocompetent cells have been termed pattern
recognition receptors.
Endotoxin, for example, interacts with cells via the pattern recognition receptor CD14. Spontaneous binding of endotoxin to
CD14 occurs at very slow rates. Lipopolysaccharide (LPS) CD14binding is greatly accelerated in the presence of an acute-phase
reactant mainly derived from the liver, lipopolysaccharidebinding protein (LBP). CD14 does not have an intracellular
domain; cells respond to endotoxin via signaling through TLR4,
which requires the presence of a secreted protein, MD-2. TLR2 in
turn is essential for signaling the proinflammatory effects of the
bacterial lipoproteins, peptidoglycan and zymosan, whereas TLR5
mediates cellular effects induced by bacterial flagellin, and TLR9
mediates effects induced by unmethylated CpG-containing oligonucleotides present in bacterial (but not eukaryotic) DNA. Different members of the TLR family can act together in activating cells
in response to pathogens; e.g., TLR2 and TLR6 cooperate in detecting certain bacterial components, including peptidoglycan.92 The

in vivo relevance of induction of an effective innate immune

response to infection has been shown with specific-TLR-deficient
mice. TLR2 knockout mice are highly susceptible to infection due
to gram-positive organisms, whereas TLR4 knockout mice have
reduced resistance to gram-negative infection.93
Designing methods to neutralize microbial products or block
their interaction with specific receptor on immune cells is an
attractive concept. Monoclonal antibodies (IC14) against CD14
have been evaluated in phase I studies.94,95 IC14 was shown to
attenuate LPS-induced clinical symptoms and strongly inhibited
LPS-induced proinflammatory cytokine release, while delaying the
release of the anti-inflammatory cytokines. The results suggest that
CD14 blockade with IC14 warrants further clinical investigation
to determine its ability to attenuate the proinflammatory response
due to infection.

FUTURE CONSIDERATIONS
The publication of the human genome will lead to advances in
genomics and proteomics in the coming decade. The possibilities
for individualized drug treatment of patients with sepsis, related
to their genotype, may become reality. New technology may allow
bedside testing of patients genotypes or determination of protein
or peptide biomarkers associated with poor outcome, to allow
targeted therapy of even the sickest patients.
It is probable that many new agents will be developed based on
the unraveling of the hostpathogen interaction. However, until
this time we must utilize currently available therapies to the best
of our knowledge. Despite huge advances, treatment of sepsis is
still dependent upon administration of appropriate antibiotics,
intravenous fluid support, and relatively crude methods of organ

support. We can only improve upon current treatment of pediatric

sepsis after there is agreement that properly conducted multicenter
clinical trials can and must be carried out in critically ill children
in order to test new therapies. To reach this goal, we should model
pediatric sepsis trials after the successful clinical trial programs
such as those that have so greatly improved survival from childhood cancer.
There have only been three large properly controlled phase III
studies in children with sepsis, none of which has recruited adequate numbers to definitively determine efficacy. Although these
and all the many adult studies except one have failed to demonstrate a significant survival advantage, there is much that can be
learned from these unsuccessful studies that is relevant to the
design of future sepsis trials. Children with severe sepsis and shock
should be enrolled in double-blind, placebo-controlled studies to
evaluate new treatments. These studies should be large enough
to minimize random error and avoid type II error. Definitions
for the target population should be explicit, reproducible, and
include illness severity scores. Protocols for both the use of
the investigational agent and conventional treatment should be
standardized. Outcomes should be clinically relevant and
predefined, and should include measures of both benefit and
harm. In addition, the analysis of results should be carried
out, both on evaluable patients and on the intent-to-treat population. Finally, a health economic evaluation of the implications
of the introduction of ever-increasingly expensive therapies
should be mandatory. Only in this way will we be likely to influence the unacceptably high mortality rate of severe sepsis in
children, with the added advantage of limiting the widespread use
of extremely expensive new therapies that have been insufficiently
evaluated.

The Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and Septic Shock

REFERENCES
1. Anderson MR, Blumer JL. Advances in the therapy for sepsis
in children. Pediatr Clin North Am 1997;44:179205.
2. Despond O, Proulx F, Carcillo JA, et al. Pediatric sepsis and
multiple organ dysfunction syndrome. Curr Opin Pediatr
2001;13:247253.
3. Hazelzet JA, Risseeuw-Appel IM, Kornelisse RF, et al.
Age-related differences in outcome and severity of DIC in
children with septic shock and purpura. Thromb Haemost
1996;76:932938.
4. Martinot A, Leclerc F, Cremer R, et al. Sepsis in neonates and
children: definitions, epidemiology, and outcome. Pediatr
Emerg Care 1997;13:277281.
5. DuPont HL, Spink WW. Infections due to gram-negative
organisms: an analysis of 860 patients with bacteremia at the
University of Minnesota Medical Center, 19581966.
Medicine (Baltimore) 1969;48:307332.
6. Goldstein B, Giroir B, Randolph A. International pediatric
sepsis consensus conference: definitions for sepsis and organ
dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:28.
7. Stoll BJ, Holman RC, Schuchat A. Decline in sepsis-associated
neonatal and infant deaths in the United States, 1979
through 1994. Pediatrics 1998;102:e18.
8. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The
epidemiology of severe sepsis in children in the United
States. Am J Respir Crit Care Med 2003;167:695701.
9. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis
Campaign: international guidelines for management of
severe sepsis and septic shock: 2008. Crit Care Med
2008;36:296-327.
10. Zaritsky AL, Nadkarni VM, Hickey RW, et al. Pediatric
Advanced Life Support Provider Manual. Dallas, TX, American
Heart Association, 2002.
11. Brierley J, Carcillo JA, Choong K, et al. Clinical practice
parameters for hemodynamic support of pediatric and
neonatal septic shock: 2007 update from the American
College of Critical Care Medicine. Crit Care Med
2009;37:666688.
12. Carcillo JA, Fields AI. Clinical practice parameters for
hemodynamic support of pediatric and neonatal patients in
septic shock. Crit Care Med 2002;30:13651378.
13. Centers for Disease Control and Prevention. Summary of
notifiable diseases United States, 2005. MMWR Morb
Mortal Wkly Rep 2007;54:18.
14. Centers for Disease Control and Prevention. Summary of
notifiable diseases United States, 2008. MMWR Morb
Mortal Wkly Rep 2010;57:19.
15. Centers for Disease Control and Prevention. Invasive
pneumococcal disease in young children before licensure of
13-valent pneumococcal conjugate vaccine United States,
2007. MMWR Morb Mortal Wkly Rep 2010;59:253.
16. Ahmed R, Hassall T, Morland B, et al. Viridans streptococcus
bacteremia in children on chemotherapy for cancer: an
underestimated problem. Pediatr Hematol Oncol
2003;20:439444.
17. Okamoto Y, Ribeiro RC, Srivastava DK, et al. Viridans
streptococcal sepsis: clinical features and complications in
childhood acute myeloid leukemia. J Pediatr Hematol Oncol
2003;25:696703.
18. Barton P, Kalil AC, Nadel S, et al. Safety, pharmacokinetics,
and pharmacodynamics of drotrecogin alfa (activated) in
children with severe sepsis. Pediatrics 2004;113:717.
19. Beutler B, Poltorak A. Sepsis and evolution of the innate
immune response. Crit Care Med 2001;29:S2S6; discussion
S-7.
20. Ulevitch RJ. New therapeutic targets revealed through
investigations of innate immunity. Crit Care Med
2001;29:S812.

11

21. Aird WC. Vascular bed-specific hemostasis: role of

endothelium in sepsis pathogenesis. Crit Care Med
2001;29:S28S34; discussion S-5.
22. Hack CE, Zeerleder S. The endothelium in sepsis: source of
and a target for inflammation. Crit Care Med
2001;29:S21S27.
23. Joyce DE, Gelbert L, Ciaccia A, et al. Gene expression profile
of antithrombotic protein c defines new mechanisms
modulating inflammation and apoptosis. J Biol Chem
2001;276:1119911203.
24. Butt W. Septic shock. Pediatr Clin North Am 2001;48:601
625, viii.
25. Tollner U, Pohlandt F. Septicemia in the newborn due
to gram-negative bacilli: risk factors, clinical symptoms,
and hematologic changes. Eur J Pediatr 1976;123:
243254.
26. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid
resuscitation in pediatric septic shock. JAMA
1991;266:12421245.
27. Carcillo JA, Planquois J-M, Goldstein B. Early markers of
infection and sepsis in newborns and children. Adv Sepsis
2006;5:118125.
28. Alonso JM, Guiyoule A, Zarantonelli ML, et al. A model of
meningococcal bacteremia after respiratory superinfection in
influenza A virus-infected mice. FEMS Microbiol Lett
2003;222:99106.
29. Mackowiak PA, Sanders CV, Thomason J. Acute
meningococcemia without meningitis in association with
influenza-like illness. South Med J 1976;69:222224.
30. Palavecino E. Community-acquired methicillin-resistant
Staphylococcus aureus infections. Clin Lab Med
2004;24:403418.
31. Graves GR, Rhodes PG. Tachycardia as a sign of early onset
neonatal sepsis. Pediatr Infect Dis 1984;3:404406.
32. Munro MJ, Walker AM, Barfield CP. Hypotensive extremely
low birth weight infants have reduced cerebral blood flow.
Pediatrics 2004;114:15911596.
33. Marshall JC, Vincent JL, Fink MP, et al. Measures, markers,
and mediators: toward a staging system for clinical sepsis.
A report of the Fifth Toronto Sepsis Roundtable, Toronto,
Ontario, Canada, October 2526, 2000. Crit Care Med
2003;31:15601567.
34. Bonsu BK, Chb M, Harper MB. Identifying febrile
young infants with bacteremia: is the peripheral white blood
cell count an accurate screen? Ann Emerg Med
2003;42:216225.
35. Carrol ED, Newland P, Riordan FA, et al. Procalcitonin as a
diagnostic marker of meningococcal disease in children
presenting with fever and a rash. Arch Dis Child
2002;86:282285.
36. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum
lactate is associated with mortality in severe sepsis
independent of organ failure and shock. Crit Care Med
2009;37:16701677.
37. Santolaya ME, Alvarez AM, Aviles CL, et al. Predictors of
severe sepsis not clinically apparent during the first twentyfour hours of hospitalization in children with cancer,
neutropenia, and fever: a prospective, multicenter trial.
Pediatr Infect Dis J 2008;27:538543.
38. Leclerc F, Cremer R, Noizet O. Procalcitonin as a diagnostic
and prognostic biomarker of sepsis in critically ill children.
Pediatr Crit Care Med 2003;4:264266.
39. Casado-Flores J, Blanco-Quiros A, Asensio J, et al. Serum
procalcitonin in children with sepsis: a comparison with
c-reactive protein and neutrophil count. Pediatr Crit Care
Med 2003;4:190195.
40. Mariscalco MM. Is plasma procalcitonin ready for prime time
in the pediatric intensive care unit? Pediatr Crit Care Med
2003;4:118119.

103.e1

PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION A Septicemia, Toxin- and Inflammation-Mediated Syndromes
41. Meisner M. Biomarkers of sepsis: clinically useful? Curr Opin
Crit Care 2005;11:473480.
42. Enguix A, Rey C, Concha A, et al. Comparison of
procalcitonin with C-reactive protein and serum amyloid for
the early diagnosis of bacterial sepsis in critically ill neonates
and children. Intensive Care Med 2001;27:211215.
43. Pulliam PN, Attia MW, Cronan KM. C-reactive protein in
febrile children 1 to 36 months of age with clinically
undetectable serious bacterial infection. Pediatrics
2001;108:12751279.
44. Somech R, Zakuth V, Assia A, et al. Procalcitonin correlates
with C-reactive protein as an acute-phase reactant in pediatric
patients. Isr Med Assoc J 2000;2:147150.
45. Sierra R, Rello J, Bailen MA, et al. C-reactive protein used as
an early indicator of infection in patients with systemic
inflammatory response syndrome. Intensive Care Med
2004;30:20382045.
46. Huang SY, Tang RB, Chen SJ, Chung RL. Serum interleukin-6
level as a diagnostic test in children with sepsis. J Chin Med
Assoc 2003;66:523527.
47. Latifi SQ, ORiordan MA, Levine AD, Stallion A. Persistent
elevation of serum interleukin-6 in intraabdominal sepsis
identifies those with prolonged length of stay. J Pediatr Surg
2004;39:15481552.
48. Neuman MI, Harper MB. Evaluation of a rapid urine antigen
assay for the detection of invasive pneumococcal disease in
children. Pediatrics 2003;112:12791282.
49. Fujimori M, Hisata K, Nagata S, et al. Efficacy of bacterial
ribosomal RNA-targeted reverse transcription-quantitative
PCR for detecting neonatal sepsis: a case control study. BMC
Pediatr 2010;10:53.
50. Tsalik EL, Jones D, Nicholson B, et al. Multiplex PCR to
diagnose bloodstream infections in patients admitted from
the emergency department with sepsis. J Clin Microbiol
2010;48:2633.
51. Lehmann LE, Hunfeld KP, Steinbrucker M, et al. Improved
detection of blood stream pathogens by real-time PCR in
severe sepsis. Intensive Care Med 2010;36:4956.
52. Dahmer MK, Randolph A, Vitali S, Quasney MW. Genetic
polymorphisms in sepsis. Pediatr Crit Care Med
2005;6:S61S73.
53. Shanley TP, Wong HR. Molecular genetics in the
pediatric intensive care unit. Crit Care Clin 2003;19:
577594.
54. Giannoulias D, Haluska GJ, Gravett MG, et al. Localization of
prostaglandin H synthase, prostaglandin dehydrogenase,
corticotropin releasing hormone and glucocorticoid receptor
in rhesus monkey fetal membranes with labor and in the
presence of infection. Placenta 2005;26:289297.
55. Gravett MG, Novy MJ, Rosenfeld RG, et al. Diagnosis of
intra-amniotic infection by proteomic profiling and
identification of novel biomarkers. JAMA 2004;292:
462469.
56. Klein LL, Freitag BC, Gibbs RS, et al. Detection of intraamniotic infection in a rabbit model by proteomics-based
amniotic fluid analysis. Am J Obstet Gynecol
2005;193:13021306.
57. Tang J, Wilson CM, Meleth S, et al. Host genetic profiles
predict virological and immunological control of HIV-1
infection in adolescents. AIDS 2002;16:22752284.
58. Buhimschi IA, Buhimschi CS. The role of proteomics in the
diagnosis of chorioamnionitis and early-onset neonatal
sepsis. Clin Perinatol 2010;37:355374.
59. Benitz WE. Adjunct laboratory tests in the diagnosis of
early-onset neonatal sepsis. Clin Perinatol 2010;37:421438.
60. Kaplan SL, Hulten KG, Gonzalez BE, et al. Three-year
surveillance of community-acquired Staphylococcus aureus
infections in children. Clin Infect Dis 2005;40:17851791.

103.e2

61. Paterson DL, Bonomo RA. Extended-spectrum betalactamases: a clinical update. Clin Microbiol Rev
2005;18:657686.
62. Ibsen LM, Bratton S, Goldstein B. Decision trees in the
management of pediatric septic shock. In: Stein F (ed)
Seminars in Pediatric Infectious Diseases. Philadelphia,
Elsevier, 2000, pp 4352.
63. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid
resuscitation in pediatric septic shock. JAMA
1991;266:12421245.
64. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of
pediatric-neonatal septic shock by community physicians is
associated with improved outcome. Pediatrics
2003;112:793799.
65. Curley MAQ, Castillo L. Nutrition and shock in pediatric
patients. N Horizons 1998;6:212225.
66. Eslami S, Abu-Hanna A, Jonge E, Keizer NF. Tight glycemic
control and computerized decision-support systems: a
systematic review. Intensive Care Med. 2009;35:15051517.
67. Lequier LL, Nikaidoh H, Leonard SR, et al. Preoperative and
postoperative endotoxemia in children with congenital heart
disease. Chest 2000;117:17061712.
68. Marshall JC, Foster D, Vincent JL, et al. Diagnostic
and prognostic implications of endotoxemia in critical
illness: results of the MEDIC study. J Infect Dis
2004;190:527534.
69. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis
for pathogenesis of the disease process. Chest
1997;112:235243.
70. van der Poll T, Keogh CV, Buurman WA, et al. Passive
immunization against tumor necrosis factor-alpha impairs
host defense during pneumococcal pneumonia in mice. Am J
Respir Crit Care Med 1997;155:603608.
71. Greenberger MJ, Strieter RM, Kunkel SL, et al. Neutralization
of IL-10 increases survival in a murine model of Klebsiella
pneumonia. J Immunol 1995;155:722729.
72. Marchant A, Deviere J, Byl B, et al. Interleukin-10 production
during septicaemia. Lancet 1994;343:707708.
73. van Deuren M, van der Ven-Jongekrijg J, Demacker PN, et al.
Differential expression of proinflammatory cytokines and
their inhibitors during the course of meningococcal
infections. J Infect Dis 1994;169:157161.
74. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation
in septic patients: restoration by IFN-gamma treatment. Nat
Med 1997;3:678681.
75. Bilgin K, Yaramis A, Haspolat K, et al. A randomized trial of
granulocytemacrophage colony-stimulating factor in
neonates with sepsis and neutropenia. Pediatrics
2001;107:3641.
76. Meisel C, Schefold JC, Pschowski R, et al. Granulocytemacrophage colony-stimulating factor to reverse sepsisassociated immunosuppression: a double-blind, randomized,
placebo-controlled multicenter trial. Am J Respir Crit Care
Med 2009;180:640648
77. Kaul R, McGeer A, Norrby-Teglund A, et al. Intravenous
immunoglobulin therapy for streptococcal toxic shock
syndrome: a comparative observational study. The
Canadian Streptococcal Study Group. Clin Infect Dis
1999;28:800807.
78. Brocklehurst P, Brearley S, Haque K, et al. The INIS Study.
International Neonatal Immunotherapy Study: non-specific
intravenous immunoglobulin therapy for suspected or proven
neonatal sepsis: an international, placebo controlled,
multicentre randomised trial. BMC Pregnancy Childbirth
2008;8:52.
79. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment
for sepsis: a critical appraisal and meta-analysis of the
literature. Crit Care Med 1995;23:14301439.

The Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and Septic Shock
80. Vincent JL, Sun Q, Dubois MJ. Clinical trials of
immunomodulatory therapies in severe sepsis and septic
shock. Clin Infect Dis 2002;34:10841093.
81. Annane D, Sebille V, Troche G, et al. A 3-level prognostic
classification in septic shock based on cortisol levels and
cortisol response to corticotropin. JAMA 2000;283:
10381045.
82. Hatherill M, Tibby SM, Hilliard T, et al. Adrenal insufficiency
in septic shock. Arch Dis Child 1999;80:5155.
83. Riordan FA, Thomson AP, Ratcliffe JM, et al. Admission
cortisol and adrenocorticotrophic hormone levels in children
with meningococcal disease: evidence of adrenal
insufficiency? Crit Care Med 1999;27:22572261.
84. Thys F, Laterre PF. Hydrocortisone in septic shock: too much,
too little, too soon? Crit Care Med 2005;33:26832684.
85. Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group.
Hydrocortisone therapy for patients with septic shock. N Engl
J Med 2008;358:111124.
86. Kennedy WA, Hoyt MJ, McCracken GH Jr. The role of
corticosteroid therapy in children with pneumococcal
meningitis. Am J Dis Child 1991;145:13741378.
87. Murad F. The 1996 Albert Lasker Medical Research Awards.
Signal transduction using nitric oxide and cyclic guanosine
monophosphate. JAMA 1996;276:11891192.
88. Cobb JP, Natanson C, Hoffman WD, et al. N omega-amino-Larginine, an inhibitor of nitric oxide synthase, raises vascular
resistance but increases mortality rates in awake canines
challenged with endotoxin. J Exp Med 1992;176:11751182.
89. Freeman BD, Cobb JP. Nitric oxide synthase as a therapeutic
target in sepsis: more questions than answers? Crit Care Med
1998;26:14691470.
90. Cobb JP, Danner RL. Nitric oxide and septic shock. JAMA
1996;275:11921196.
91. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of
the innate immune response. Nature 2000;406:782787.
92. Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire
for pattern recognition of pathogens by the innate immune
system is defined by cooperation between toll-like receptors.
Proc Natl Acad Sci USA 2000;97:1376613771.
93. Takeuchi O, Hoshino K, Akira S. Cutting edge: TLR2-deficient
and MyD88- deficient mice are highly susceptible to
Staphylococcus aureus infection. J Immunol
2000;165:53925396.
94. Verbon A, Dekkers PE, ten Hove T, et al. IC14, an anti-CD14
antibody, inhibits endotoxin-mediated symptoms and
inflammatory responses in humans. J Immunol
2001;166:35993605.
95. Reinhart K, Gluck T, Ligtenberg J, et al. CD14 receptor
occupancy in severe sepsis: results of a phase I clinical trial
with a recombinant chimeric CD14 monoclonal antibody
(IC14). Crit Care Med 2004;32:11001108.
96. Angus DC, Birmingham MC, Balk RA, et al. E5 murine
monoclonal antiendotoxin antibody in gram-negative sepsis:
a randomized controlled trial. E5 Study Investigators. JAMA
2000;283:17231730.
97. Ziegler EJ, Fisher CJ Jr, Sprung CL, et al. Treatment of
gram-negative bacteremia and septic shock with HA-1A
human monoclonal antibody against endotoxin:
a randomized, double-blind, placebo-controlled trial.
The HA-1A Sepsis Study Group. N Engl J Med
1991;324:429436.
98. McCloskey RV, Straube RC, Sanders C, et al. Treatment of
septic shock with human monoclonal antibody HA-1A. A
randomized, double-blind, placebo-controlled trial. CHESS
Trial Study Group. Ann Intern Med 1994;121:15.
99. Derkx B, Wittes J, McCloskey R. Randomized, placebocontrolled trial of HA-1A, a human monoclonal antibody to
endotoxin, in children with meningococcal septic shock.

100.

101.

102.

103.

104.

105.

106.
107.

108.

109.

110.

111.

112.

113.
114.

115.

116.

11

European Pediatric Meningococcal Septic Shock Trial Study

Group. Clin Infect Dis 1999;28:770777.
Levin M, Quint PA, Goldstein B, et al. Recombinant
bactericidal/permeability increasing protein (rBPI21)
as adjunctive treatment for children with severe
meningococcal sepsis: a randomised trial. rBPI21
Meningococcal Sepsis Study Group (see comment). Lancet
2000;356:961967.
Wu A, Hinds CJ, Thiemermann C. High-density lipoproteins
in sepsis and septic shock: metabolism, actions, and
therapeutic applications. Shock 2004;21:210221.
Hackam DG, Mamdani M, Li P, et al. Statins and sepsis in
patients with cardiovascular disease: a population-based
cohort analysis. Lancet 2006;367:413418.
Aoki H, Kodama M, Tani T, et al. Treatment of sepsis by
extracorporeal elimination of endotoxin using polymyxin
B-immobilized fiber. Am J Surg 1994;167:412417.
Gardlund B, Sjolin J, Nilsson A, et al. Plasmapheresis in the
treatment of primary septic shock in humans. Scand J Infect
Dis 1993;25:757761.
Hoffmann JN, Hartl WH, Deppisch R, et al. Hemofiltration in
human sepsis: evidence for elimination of
immunomodulatory substances. Kidney Int
1995;48:15631570.
Pollack M. Blood exchange and plasmapheresis in sepsis and
septic shock. Clin Infect Dis 1992;15:431433.
Ronco C, Bellomo R, Homel P, et al. Effects of different doses
in continuous veno-venous haemofiltration on outcomes of
acute renal failure: a prospective randomised trial. Lancet
2000;356:2630.
Reeves JH, Butt WW, Shann F, et al. Continuous
plasmafiltration in sepsis syndrome: Plasmafiltration in Sepsis
Study Group. Crit Care Med 1999;27:20962104.
van Deuren M, Frieling JT, van der Ven-Jongekrijg J, et al.
Plasma patterns of tumor necrosis factor-alpha (TNF) and
TNF soluble receptors during acute meningococcal infections
and the effect of plasma exchange. Clin Infect Dis
1998;26:918923.
Morgera S, Rocktaschel J, Haase M, et al. Intermittent high
permeability hemofiltration in septic patients with acute renal
failure. Intensive Care Med 2003;29:19891995.
Antonelli M, Fumagalli R, Cruz DN, Brienza N, Giunta F;
EUPHAS Study Group. PMX endotoxin removal in the
clinical practice: results from the EUPHAS trial. Contrib
Nephrol 2010;167:8390.
Marshall JC. Such stuff as dreams are made on: mediatordirected therapy in sepsis. Nat Rev Drug Discov
2003;2:391405.
Fischer GW, Crumrine MH, Jennings PB. Experimental
Escherichia coli sepsis in rabbits. J Pediatr 1974;85:117119.
Panacek EA, Marshall JC, Albertson TE, et al. Efficacy and
safety of the monoclonal anti-tumor necrosis factor antibody
F(ab)2 fragment afelimomab in patients with severe sepsis
and elevated interleukin-6 levels. Crit Care Med
2004;32:21732182.
Opal SM, Fisher CJ Jr, Dhainaut JF, et al. Confirmatory
interleukin-1 receptor antagonist trial in severe sepsis: a phase
III, randomized, double-blind, placebo-controlled,
multicenter trial. The Interleukin-1 Receptor Antagonist
Sepsis Investigator Group. Crit Care Med 1997;25:1115
1124.
Fisher CJ Jr, Dhainaut JF, Opal SM, et al. Recombinant
human interleukin 1 receptor antagonist in the treatment of
patients with sepsis syndrome. Results from PART II Clinical
Syndromes & Cardinal Features of ID: Approach to Diagnosis
& Initial Management a randomized, double-blind, placebocontrolled trial. Phase III rhIL-1ra Sepsis Syndrome Study
Group. JAMA 1994;271:18361843.

103.e3

PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management
SECTION A Septicemia, Toxin- and Inflammation-Mediated Syndromes
117. Bernard GR, Wheeler AP, Russell JA, et al. The effects of
ibuprofen on the physiology and survival of patients with
sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med
1997;336:912918.
118. Arons MM, Wheeler AP, Bernard GR, et al. Effects of
ibuprofen on the physiology and survival of hypothermic
sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med
1999;27:699707.
119. Staubach KH, Schroder J, Stuber F, et al. Effect of
pentoxifylline in severe sepsis: results of a randomized,
double-blind, placebo-controlled study. Arch Surg
1998;133:94100.
120. Lauterbach R, Pawlik D, Kowalczyk D, et al. Effect of
the immunomodulating agent, pentoxifylline, in the
treatment of sepsis in prematurely delivered infants: a
placebo-controlled, double-blind trial. Crit Care Med
1999;27:807814.
121. Lauterbach R, Zembala M. Pentoxifylline reduces plasma
tumour necrosis factoralpha concentration in premature
infants with sepsis. Eur J Pediatr 1996;155:404409.
122. Taylor FB Jr, Chang A, Ruf W, et al. Lethal E. coli septic shock
is prevented by blocking tissue factor with monoclonal
antibody. Circ Shock 1991;33:127134.
123. Abraham E. Tissue factor inhibition and clinical trial results
of tissue factor pathway inhibitor in sepsis. Crit Care Med
2000;28(Suppl):S31S33.
124. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of
tifacogin (recombinant tissue factor pathway inhibitor) in
severe sepsis: a randomized controlled trial. JAMA
2003;290:238247.
125. Inthorn D, Hoffmann JN, Hartl WH, et al. Effect of
antithrombin III supplementation on inflammatory response
in patients with severe sepsis. Shock 1998;10:9096.
126. Wiedermann CJ, Hoffmann JN, Juers M, et al. High-dose
antithrombin III in the treatment of severe sepsis in patients
with a high risk of death: efficacy and safety. Crit Care Med
2006;34:285292.

103.e4

127. Bernard GR, Ely EW, Wright TJ, et al. Safety and dose
relationship of recombinant human activated protein C for
coagulopathy in severe sepsis. Crit Care Med
2001;29:20512059.
128. Nadel S, Goldstein B, Peters M, et al. Efficacy of drotrecogin
alfa (activated) for the treatment of pediatric severe sepsis.
Crit Care Med 2005;33:A152.
129. Zenz W, Zoehrer B, Levin M, et al. Use of recombinant tissue
plasminogen activator in children with meningococcal
purpura fulminans: a retrospective study. Crit Care Med
2004;32:17771780.
130. Vincent JL, Spapen H, Bakker J, et al. Phase II multicenter
clinical study of the platelet-activating factor receptor
antagonist BB-882 in the treatment of sepsis. Crit Care Med
2000;28:638642.
131. Poeze M, Froon AH, Ramsay G, et al. Decreased organ
failure in patients with severe SIRS and septic shock treated
with the platelet-activating factor antagonist TCV-309: a
prospective, multicenter, double-blind, randomized phase II
trial. TCV-309 Septic Shock Study Group. Shock
2000;14:421428.
132. Dhainaut JF, Tenaillon A, Hemmer M, et al. Confirmatory
platelet-activating factor receptor antagonist trial in patients
with severe gram-negative bacterial sepsis: a phase III,
randomized, double-blind, placebo-controlled, multicenter
trial. BN 52021 Sepsis Investigator Group. Crit Care Med
1998;26:19631971.
133. Schuster DP, Metzler M, Opal S, et al. Recombinant plateletactivating factor acetylhydrolase to prevent acute respiratory
distress syndrome and mortality in severe sepsis: phase IIb,
multicenter, randomized, placebo-controlled, clinical trial.
Crit Care Med 2003;31:16121619.
134. Opal S, Laterre PF, Abraham E, et al. Recombinant human
platelet-activating factor acetylhydrolase for treatment of
severe sepsis: results of a phase III, multicenter, randomized,
double-blind, placebo-controlled, clinical trial. Crit Care Med
2004;32:332341.